1. Field of the Invention
The present invention relates to novel compounds that function as enzyme inhibitors, and particularly to a new class of non-peptidic inhibitors of proteolytic enzymes.
2. Related Art
Proteases are enzymes that cleave proteins at single, specific peptide bonds. Proteases can be classified into four generic classes: serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers et al., J. Biol. Chem. 257:7086 (1982)). Proteases are essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots, reproduction and the immune reaction to foreign cells and organisms. Aberrant proteolysis is associated with a number of disease states in man and other mammals. The human neutrophil proteases, elastase and cathepsin G, have been implicated as contributing to disease states marked by tissue destruction. These disease states include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs, Sandler, ed., University Park Press, Baltimore, (1980)). Additional proteases such as plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, and kallikreins play key roles in normal biological functions of mammals. In many instances, it is beneficial to disrupt the function of one or more proteolytic enzymes in the course of therapeutically treating a mammal.
Serine proteases include such enzymes as elastase (human leukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, chymotrypsin, trypsin, thrombin, factor Xa and kallikreins.
Human leukocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states. Cathepsin G is another human neutrophil serine protease. Compounds with the ability to inhibit the activity of these enzymes are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. Chymotrypsin and trypsin are digestive enzymes. Inhibitors of these enzymes are useful in treating pancreatitis. Inhibitors of urokinase and plasminogen activator are useful in treating excessive cell growth disease states, such as benign prostatic hypertrophy, prostatic carcinoma and psoriasis.
The serine protease thrombin occupies a central role in hemostasis and thrombosis, and as a multifactorial protein, induces a number of effects on platelets, endothelial cells, smooth muscle cells, leukocytes, the heart, and neurons (Tapparelli et al., Trends in Pharmacological Sciences 14:366-376 (1993); Lefkovits and Topol, Circulation 90(3):1522-1536 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)). Activation of the coagulation cascade through either the intrinsic pathway (contact activation) or the extrinsic pathway (activation by exposure of plasma to a non-endothelial surface, damage to vessel walls or tissue factor release) leads to a series of biochemical events that converge on thrombin. Thrombin cleaves fibrinogen ultimately leading to a hemostatic plug (clot formation), potently activates platelets through a unique proteolytic cleavage of the cell surface thrombin receptor (Coughlin, Seminars in Hematology 31(4):270-277 (1994)), and autoamplifies its own production through a feedback mechanism. Thus, inhibitors of thrombin function have therapeutic potential in a host of cardiovascular and non-cardiovascular diseases, including: myocardial infarction; unstable angina; stroke; restenosis; deep vein thrombosis; disseminated intravascular coagulation caused by trauma, sepsis or tumor metastasis; hemodialysis; cardiopulmonary bypass surgery; adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration; metastasis; hypercoagulability during chemotherapy; Alzheimer""s disease; Down""s syndrome; fibrin formation in the eye; and wound healing. Other uses include the use of said thrombin inhibitors as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents.
Factor Xa is another serine protease in the coagulation pathway. Factor Xa associates with factor Va and calcium on a phospholipid membrane thereby forming a prothrombinase complex. This prothrombinase complex then converts prothrombin to thrombin (Claeson, Blood Coagulation and Fibrinolysis 5:411-436 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)). Inhibitors of factor Xa are thought to offer an advantage over agents that directly inhibit thrombin since direct thrombin inhibitors still permit significant new thrombin generation (Lefkovits and Topol, Circulation 90(3):1522-1536 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)).
A need continues to exist for non-peptidic compounds that are potent and selective protease inhibitors, and which possess greater bioavailability and fewer side-effects than currently available protease inhibitors. Accordingly, new classes of potent protease inhibitors, characterized by potent inhibitory capacity and low mammalian toxicity, are potentially valuable therapeutic agents for a variety of conditions, including treatment of a number of mammalian proteolytic disease states.
Ozawa, H. et al., Yakugaku Zasshi, 95(8):966-74 (1975) describe a number of benzyl- and benzylidine aminoguanidine and amidinohydrazone compounds. For example, the following salts are described: 
The compounds were tested for their effect on blood pressure in rats.
Augstein, J. et al., J. Med. Chem., 10(3):391-400 (1967) discloses a series of aryloxyalkylamino-guanidines of the formula: 
In some compounds R1 is methoxy, while R2 is hydrogen and R3 and R4 are either hydrogen or methyl. Several such aminoguanidines containing chloro and methyl substituents in the aromatic ring were shown to possess adrenergic neuron blocking properties and to inhibit dopamine xcex2-oxidase in vitro. The synthesis and testing of aminoguanidines containing one or more methoxy substituents in the aromatic ring is also disclosed.
The present invention is directed to novel compounds having Formula I (below). Also provided are processes for preparing compounds of Formula I. The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity.
The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
Also provided are methods of inhibiting or treating aberrant proteolysis in a mammal, and methods for treating myocardial infarction; unstable angina; stroke; restenosis; deep vein thrombosis; disseminated intravascular coagulation caused by trauma, sepsis or tumor metastasis; hemodialysis; cardiopulmonary bypass surgery; adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration; metastasis; hypercoagulability during chemotherapy; Alzheimer""s disease; Down""s syndrome; fibrin formation in the eye; and wound healing. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents.
The invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
Compounds of the present invention include compounds of Formula I: 
or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:
R1 is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
Z is one of xe2x80x94NR10SO2xe2x80x94, xe2x80x94SO2NR10xe2x80x94, xe2x80x94NR10C(RyRz)xe2x80x94, xe2x80x94C(RyRz)NR10xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94OC(RyRz)xe2x80x94, xe2x80x94C(RyRz)Oxe2x80x94, xe2x80x94NR10COxe2x80x94 or xe2x80x94CONR10xe2x80x94;
Ry and Rz are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
R2, R3 and R4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, xe2x80x94CO2Rx, xe2x80x94CH2ORx or xe2x80x94ORx, or when present on adjacent carbon atoms, R2 and R3 may also be taken together to form one of xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)qxe2x80x94, where q is from 2 to 6, and R4 is defined as above;
Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
Y is one of xe2x80x94Oxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CHR10xe2x80x94 or a covalent bond;
X is oxygen or NR9;
R9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl;
R6 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl, or alternatively, R6 and R12 taken together to form xe2x80x94(CH2)wxe2x80x94, where w is 1-5;
R7 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino, provided that n is other than zero when R7 is hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino;
R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
or R7 and R8 are taken together to form xe2x80x94(CH2)yxe2x80x94, where y is zero (a bond), 1 or 2, while R11 and R12 are defined as above; or R7 and R12 are taken together to form xe2x80x94(CH2)qxe2x80x94, where q is zero (a bond), or 1 to 8, while R8 and R11 are defined as above; or R8 and R11 are taken together to form xe2x80x94(CH2)rxe2x80x94, where r is 2-8, while R7 and R12 are defined as above;
R10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxy(C2-10)alkyl, amino(C2-10)alkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or xe2x80x94CO2Rw;
Rw is alkyl, cycloalkyl, phenyl, benzyl, 
xe2x80x83where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
n is from zero to 8; and m is from zero to 4.
A preferred group of compounds falling within the scope of the present invention include compounds of Formula I wherein:
R1 is one of C6-10 aryl, pyridinyl, thiophenyl (i.e., thiophene), quinazolinyl, quinolinyl or tetrahydroquinolinyl, any of which is optionally substituted by one or two of hydroxy, nitro, trifluoromethyl, halogen, C1-6 alkyl, C6-10 aryl, C1-6 alkoxy, C6-10 ar(C1-6)alkoxy, C1-6 aminoalkyl, C1-6 aminoalkoxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, C1-6 hydroxyalkyl, C2-6 hydroxyalkoxy, (C1-6)alkoxy(C2-6)alkoxy, mono- and di-C1-4 alkylamino(C2-6)alkoxy, C2-10 mono(carboxyalkyl)amino, di(C2-10 carboxyalkyl)amino, C6-14 ar(C1-6)alkoxycarbonyl, C2-6 alkynylcarbonyl, C1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6)alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, C6-10 arylsulfonamido, C6-10 ar(C1-6)alkylsulfonamido, amidino, guanidino, C1-6 alkyliminoamino, formyliminoamino, C2-6 carboxyalkoxy, C2-6 carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy, perfluoroethoxy and R13R14NSO2xe2x80x94;
R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, alkoxy(C2-10)alkyl, mono- and di-alkylamino(C2-10)alkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a three to seven membered ring, optionally containing one or more heteroatoms in addition to said nitrogen, such as oxygen, sulfur, or nitrogen (NR15), said ring being preferably saturated, and said ring having one or two optional substituents selected from the group consisting of hydroxy, acyloxy, alkoxy, aryloxy, amino, mono- and di-alkylamino, acylamino, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, alkoxy((2-10)alkyl, mono- and di-alkylamino(C2-10)alkyl, carboxy, alkoxycarbonyl, carboxamido, formyl, alkanoyl, aroyl, aralkanoyl, sulfonyl, alkylsulfonyl, alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, and phosphinyl, and wherein R15 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, alkoxy(C2-10)alkyl, mono- and di-alkylamino(C2-10)alkyl, carboxy, alkoxycarbonyl, carboxamido, formyl, alkanoyl, aroyl, aralkanoyl, sulfonyl, alkylsulfonyl, alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, and phosphinyl;
Z is one of xe2x80x94SO2Oxe2x80x94, xe2x80x94SO2NR10xe2x80x94, xe2x80x94C(RyRz)Oxe2x80x94 or xe2x80x94OC(RyRz)xe2x80x94, where Ry and Rz are each hydrogen;
R2, R3 and R4 are independently one of hydrogen, C1-4 alkyl, C3-8 cycloalkyl, phenyl, benzyl, trifluoromethyl, halogen, hydroxy(C1-4)alkyl, cyano, nitro, carboxamido, carboxy, C1-4 alkoxycarbonyl, C1-4 alkoxymethyl or C1-4 alkoxy; or alternatively, R2 and R3, when present on adjacent carbon atoms, may also be taken together to form one of xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)qxe2x80x94, where q is from 2 to 6, and R4 is as defined above;
Y is one of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR10xe2x80x94, or a covalent bond;
Ra, Rb and Rc are each one of hydrogen, C1-4 alkyl, hydroxy, C1-4 alkoxy, phenoxy, C1-4 alkyloxycarbonyl, benzyloxycarbonyl, cyano, 
xe2x80x83where Rh is benzyl, methyl, ethyl, isopropyl, sec-butyl or t-butyl, and where Rf is hydrogen or C1-6 alkyl;
R6 is one of hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl, C2-10 aminoalkyl, mono(C1-4)alkylamino(C2-8)alkyl, di(C1-4)alkylamino(C2-8)alkyl or C2-10 carboxyalkyl;
R7, R8, R11 and R12 are independently one of hydrogen, C1-6 alkyl, C2-10 carboxyalkyl or C2-10 hydroxyalkyl, or R7 and R8 are taken together to form xe2x80x94(CH2)yxe2x80x94 where y is zero, 1 or 2, while R11 and R12 are defined as above; or R7 and R12 are taken together to form xe2x80x94(CH2)qxe2x80x94, where q is zero (a bond), or 1, 2 or 3, while R8 and R11 are defined as above; or R8 and R11 are taken together to form xe2x80x94(CH2)rxe2x80x94, where r is 2, 3, or 4, while R7 and R12 are defined as above;
R9 is hydrogen, or C1-10 alkyl, optionally substituted with amino, mono(C1-4)alkylamino, C1-6 alkoxy, hydroxy, carboxy, phenyl, C1-4 alkyloxycarbonyl, C6-10 ar(C1-4)alkoxycarbonyl, C1-6 acylamino, cyano or trifluoromethyl;
R10, in each instance, is independently hydrogen, C1-6 alkyl, benzyl, phenyl, C2-10 hydroxyalkyl, C2-10 aminoalkyl, C1-4 monoalkylamino(C2-8)alkyl, C1-4 dialkylamino(C2-8)alkyl or C2-10 carboxyalkyl;
n is from zero to 8; and m is from zero to 4.
In this preferred embodiment, R1 can be one of C6-10 aryl, pyridinyl, thiophenyl (i.e., thiophene), quinazolinyl, quinolinyl or tetrahydroquinolinyl, any of which is optionally substituted by one or two of hydroxy, nitro, trifluoromethyl, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C1-6 aminoalkoxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, C1-6 hydroxyalkyl, C2-6 hydroxyalkoxy, C2-10 mono(carboxyalkyl)amino, bis(C2-10 carboxyalkyl)amino, C6-14 ar(C1-6)alkoxycarbonyl, C2-6 alkynylcarbonyl, C1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, amidino, guanidino, C1-6 alkyliminoamino, formyliminoamino, C2-6 carboxyalkoxy, C2-6 carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy, and perfluoroethoxy.
An especially preferred group of compounds include compounds of Formula I wherein:
R1 is one of phenyl, naphthyl, pyridyl, thiophenyl, quinolinyl or isoquinolinyl, optionally substituted by one or two of chloro, methoxy, methyl, trifluoromethyl, cyano, nitro, amino or dimethylamino;
Z is one of xe2x80x94SO2Oxe2x80x94, xe2x80x94SO2NR10xe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94OCH2xe2x80x94;
R2 and R3 are hydrogen or C1-4 alkyl, or R2 and R3 may also be taken together to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
R4 is one of hydrogen, methyl, methoxy or trifluoromethyl;
Y is one of O, NR10 or a covalent bond;
Ra, Rb and Rc are hydrogen, hydroxy, 
xe2x80x83where Rh is benzyl or t-butyl, and where Rf is hydrogen or methyl;
R6 is hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, or methylamino(C2-8)alkyl;
R7, R8, R11 and R12 are independently one of hydrogen, C1-6 alkyl, C2-10 hydroxyalkyl or C2-10 carboxyalkyl, or R7 and R8 are taken together to form xe2x80x94(CH2)yxe2x80x94 where y is zero, 1 or 2, while R11 and R12 are defined as above; or R7 and R12 are taken together to form xe2x80x94(CH2)qxe2x80x94, where q is zero (a bond), or 1, 2 or 3, while R8 and R11 are defined as above; or R8 and R11 are taken together to form xe2x80x94(CH2)rxe2x80x94, where r is 2, 3 or 4, while R7 and R12 are defined as above;
R9 is hydrogen or C1-4 alkyl;
R10, in each instance, is independently hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, methylamino(C2-8)alkyl;
n is from zero to 4; and m is zero, 1, 2 or 3.
Another especially preferred group of compounds include compounds of Formula I wherein:
R1 is phenyl, substituted by one of alkylsulfonyl, arylsulfonyl and R13R14NSO2xe2x80x94, where R13 and R14 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2 6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholinosulfonyl, N-piperazinylsulfonyl (optionally Nxe2x80x2 substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of hydroxy, C1-8 alkanoyloxy, C1-6 alkoxy, C6-10 aryloxy, amino, mono- and di-C1-6 alkylamino, C1-8 alkanoylamino, C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, heterocycle, heterocycloalkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, formyl, C1-6 alkanoyl, C6-10 aroyl, C6-10 ar(C1-4)alkanoyl, sulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl;
Z is one of xe2x80x94SO2Oxe2x80x94, xe2x80x94SO2NR10xe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94OCH2xe2x80x94;
R2 and R3 are hydrogen or C1-4 alkyl, or R2 and R3 may also be taken together to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
R4 is one of hydrogen, methyl, methoxy or trifluoromethyl;
Y is one of O, NR10 or a covalent bond;
Ra, Rb and Rc are hydrogen, hydroxy, 
xe2x80x83where Rh is benzyl or t-butyl, and where Rf is hydrogen or methyl;
R6 is hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, or methylamino(C2-8)alkyl;
R7, R8, R11 and R12 are independently one of hydrogen, C1-6 alkyl, C2-10 hydroxyalkyl or C2-10 carboxyalkyl, or R7 and R8 are taken together to form xe2x80x94(CH2)yxe2x80x94 where y is zero, 1 or 2, while R11 and R12 are defined as above; or R7 and R12 are taken together to form xe2x80x94(CH2)qxe2x80x94, where q is zero (a bond), or 1, 2 or 3, while R8 and R11 are defined as above; or R8 and R11 are taken together to form xe2x80x94(CH2)rxe2x80x94, where r is 2, 3 or 4, while R7 and R12 are defined as above;
R9 is hydrogen or C1-4 alkyl;
R10, in each instance, is independently hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C1-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, methylamino(C2-8)alkyl;
n is from zero to 4; and m is zero, 1, 2 or 3.
The moiety xe2x80x94Zxe2x80x94R1 of Formula I is attached to the benzene ring in a position ortho-, meta- or para- to Y, with the meta-position being preferred.
Preferred compounds of the present invention are those of Formula I wherein Y is one of divalent oxygen (xe2x80x94Oxe2x80x94), xe2x80x94NR10xe2x80x94 or a covalent bond, most preferably xe2x80x94Oxe2x80x94 and Z is one of xe2x80x94SO2NR10xe2x80x94, xe2x80x94SO2Oxe2x80x94 or xe2x80x94CH2Oxe2x80x94, most preferably xe2x80x94SO2Oxe2x80x94.
Preferred compounds of the present invention are those of Formula I wherein R1 is one of C1-12 alkyl, especially C3-8 alkyl, C4-7 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl or C6-14 aryl, especially C6-10 aryl, any of which is optionally substituted. Substituents that can be optionally present on the R1 moieties include one or more, preferably one or two, of hydroxy, nitro, trifluoromethyl, halogen, alkoxy, aralkoxy, aminoalkoxy, aminoalkyl, hydroxyalkyl, hydroxyalkoxy, alkoxyalkoxy, mono- and di-alkylaminoalkoxy, cyano, aryl, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, carboxyalkoxy, mono(hydroxyalkyl)amino, bis(hydroxyalkyl)amino, mono(carboxyalkyl)amino, bis(carboxyalkyl)amino, alkoxycarbonylamino, alkoxycarbonyl, aralkoxycarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfinyl, alkylsulfonamido, arylsulfonamido, aralkylsulfonamido, amidino, guanidino, alkyliminoamino, formyliminoamino, trifluoromethoxy, perfluoroethoxy or an aminosulfonyl group R13R14NSO2xe2x80x94, where R13 and R14 are as defined above. A further substituent on aryl, cycloalkyl, alkenyl, alkynyl and aralkyl moieties of R1 includes one or more, preferably one or two, alkyl moieties.
Preferred values of optional substituents on R1 include hydroxy, nitro, trifluoromethyl, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C6-10 aryl, C6-10 ar(C1-6)alkoxy, biphenyl(C1-6)alkoxy C1-6 aminoalkoxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, C1-6 hydroxyalkyl, C2-10 mono(carboxyalkyl)amino, bis(C2-10 carboxyalkyl)amino, C6-14 ar(C1-6)alkoxycarbonyl, C2-6 alkynylcarbonyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, amidino, guanidino, C1-6 alkyliminoamino, formyliminoamino, C2-6 carboxyalkoxy, carboxyalkylamino, cyano, trifluoromethoxy, and perfluoroethoxy.
Additional preferred values of optional substituents on R1 include C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6)alkylsulfonyl, C6-10 arylsulfonamido, C6-10 ar(C1-6)alkylsulfonamido, N-morpholinosulfonyl, and R13R14NSO2xe2x80x94, where R13 and R14 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C24)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholinosulfonyl, N-piperazinylsulfonyl (optionally Nxe2x80x2 substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of hydroxy, C1-8 alkanoyloxy, C1-6 alkoxy, C6-10 aryloxy, amino, mono- and di-C1-6 alkylamino, C1-8 alkanoylamino, C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, heterocycle, heterocycloalkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, formyl, C1-6 alkanoyl, C6-10 aroyl, C6-10 ar(C1-4)alkanoyl, sulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl.
An additional preferred group of compounds are those compounds of Formula I wherein R1 is heteroaryl or substituted heteroaryl. Preferred R1 heteroaryl groups include pyridyl, pyrazolyl, thiophenyl, chromenyl, benzoxazolyl, benzthiadiazolyl, quinazolinyl, quinolinyl, isoquinolinyl and tetrahydroquinolinyl, with thiophenyl, quinazolinyl, quinolinyl and tetrahydroquinolinyl being more preferred and thiophenyl, isoquinolinyl and quinolinyl especially preferred. Preferred compounds when R1 is substituted heteroaryl include those compounds having one of the heteroaryl groups mentioned as preferred that have one or more, preferably one or two, substituents that are listed in the preceding paragraph. Preferred substituents when R1 is substituted heteroaryl include one or more substituents, preferably 1 to 3 substituents, independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, amidino, guanidino, carboxyalkoxy, carboxyalkylamino, amino, mono(C1-6)alkylamino and/or di(C1-6)alkylamino.
Useful values of R1 include phenyl, chlorophenyl, iodophenyl, dichlorophenyl, bromophenyl, trifluoromethylphenyl, methylsulfonylphenyl, di(trifluoromethyl)phenyl, methylphenyl, t-butylphenyl, methoxyphenyl, dimethoxyphenyl, hydroxyphenyl, carboxyphenyl, aminophenyl, methylaminophenyl, n-butylaminophenyl, amidinophenyl, guanidinophenyl, formyliminoaminophenyl, acetimidoylaminophenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, carboxymethoxyphenyl, naphthyl, hydroxynaphthyl, cyclohexyl, cyclopentyl, 2-propylbutyl, 5-chloro-2-methoxyphenyl, 2-cyanophenyl, 2-(N-hydroxy)aminophenyl, 2-(4-biphenylmethoxy)phenyl, 2-(3-biphenylmethoxy)phenyl, benzyl, 3-(6-(2,3-dihydro-1,1-dioxobenzo[b]thiophene)phenyl, 2-(phenylsulfonyl)phenyl, 2,4-bis(methylsulfonyl)phenyl, and 2-chloro-4-methylsulfonylphenyl. Additional useful values include 8-quinolinyl, 5-methyl-8-quinolinyl, 4-benzo-2,1,3-thiadiazolyl, 5-chloro-2-thiophenyl, 5-chloro-1,3-dimethyl-4-pyrazolyl, pyridyl, isoquinolinyl, and tetrahydroquinolinyl.
Useful values of R1, when R1 is phenyl substituted by R13R14NSO2xe2x80x94 include 2-(N-methylphenethylaminosulfonyl)phenyl, bis(2-methoxyethyl)aminosulfonylphenyl, 2-N-methyl-(3,4-dimethoxyphenyl)ethylaminosulfonylphenyl, N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenyl, 2-(N-methyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenyl, 2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenyl, 2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenyl, 2-(N-methyl-N-(4-methoxyphenyl)aminosulfonyl)phenyl, 2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenyl, 2-(N-(2-cyanoethyl)-N-(3-pyridylmethyl)aminosulfonyl)phenyl, 2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)phenyl, 2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenyl, 2-(N-methyl-N-(2-(4-pyridyl)ethyl)aminosulfonyl)phenyl, 2-(N-(ethoxycarbonylmethyl)-N-(2-pyridylmethyl)aminosulfonyl)phenyl, 2-(N,N-,bis-(ethoxycarbonylmethyl)aminosulfonyl)phenyl, 2-(N,N-bis-(carboxymethyl)aminosulfonyl)phenyl, 2-(N-methyl-N-(4-carboxyphenyl)aminosulfonyl)phenyl, 2-(N-(2-carboxyethyl)-N-benzylaminosulfonyl)phenyl, 2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenyl, 2-(N-ethyl-N-(1-benzyl-3-pyrroldinyl)aminosulfonyl)phenyl, 2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenyl, 2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenyl, 2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenyl, 2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenyl, 2-(2-(4-morpholinyl)ethylaminosulfonyl)phenyl, 2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenyl, N-ethyl-3,4-(methylenedioxy)anilinosulfonylphenyl, 2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenyl, and 2-(4-pyridylmethyl-aminosulfonyl)phenyl.
Further useful values of R1, when R1 is phenyl substituted by R13R14NSO2xe2x80x94 include 2-morpholinylsulfonylphenyl, 2-(acetylpiperazinylsulfonyl)phenyl, 2-(4-ethyloxycarbonyl)piperidinylsulfonyl, 2-(4-carboxyl)piperidinylsulfonylphenyl, 3-ethoxycarbonyl-1-piperidinosulfonyl)phenyl, 3-carboxypiperidinosulfonyl)phenyl, 2-methoxycarbonyl-1-pyrrolidinosulfonyl)phenyl, 2-carboxy-1-pyrrolidinosulfonyl)phenyl, 2-(4-methylsulfonylpiperazin-1-ylsulfonyl)phenyl, 2-(4-(2-pyrimidinyl)piperazin-1-ylsulfonyl)phenyl, 2-(4-ethylpiperazin-1-ylsulfonyl)phenyl, 2-(4-(piperidin-1-yl)piperidin-1-ylsulfonyl)phenyl, 2-(4-(ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)phenyl, 2-(4-(carboxymethyl)piperazin-1-ylsulfonyl)phenyl, 2-(4-(2-pyridyl)piperazinyl-sulfonyl)phenyl, 2-(4-phenylpiperazinylsulfonyl)phenyl, 2-(4-benzylpiperazinylsulfonyl)phenyl, 2-(4-(2-methoxyphenyl)piperazinylsulfonyl)phenyl, 2-(4-methylpiperazinylsulfonyl)phenyl, 2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenyl, and 2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenyl.
The groups R2, R3 and R4 in Formula I substitute for any remaining hydrogen atoms on the benzene ring after allowing for attachment of the moiety xe2x80x94Zxe2x80x94R1. Preferred compounds are those where R2, R3 and R4 are independently hydrogen, C1-4 alkyl, C4-7 cycloalkyl, C6-14 aryl, especially C6-10 aryl, C6-10 ar(C1-4)alkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamide, carboxy, alkoxycarbonyl, carboxymethyl, alkoxycarbonylmethyl, or cycloalkyloxycarbonyl.
Alternatively, R2 and R3, when attached to adjacent carbon atoms on the benzene ring, are one of xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)qxe2x80x94, where q is from 2 to 6, thereby forming a fused ring. Preferred values of R2 together with R3 include xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x80x94. When R2 and R3 together form a fused ring, R4 is preferably hydrogen.
Useful values of R2, R3 and R4 include hydrogen, methyl, ethyl, chloro, bromo, trifluoromethyl, hydroxymethyl, methoxy, ethoxy, carboxamide, nitro, phenyl, cyclopropyl, hydroxy, isopropyl, methoxycarbonyl, ethoxycarbonyl and benzyl. Useful values of R2, R3 and R4 also include R2 and R3 together forming xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and R4 being hydrogen.
Preferred compounds are those of Formula I, where R6 is hydrogen or C1-6 alkyl.
Preferred compounds are those of Formula I, where R7, R8, R11 and R12 are independently one of hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl or C2-7 carboxyalkyl. Useful values of R7, R8, R11 and R12 include hydrogen, methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-carboxymethyl, 3-carboxyethyl and 4-carboxypropyl. Additional preferred compounds are those wherein R7 and R8 are taken together to form xe2x80x94(CH2)yxe2x80x94 where y is most preferably 2. Another group of preferred compounds are those where R8 and R11 are taken together to form xe2x80x94(CH2)rxe2x80x94 where r is most preferably 2.
Preferred compounds are those of Formula I, wherein R9 is hydrogen or C1-6 alkyl, optionally substituted by one, two or three, preferably one, of amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboalkoxy, phenyl, cyano, trifluoromethyl, acetylamino, pyridyl, thiophenyl, furyl, pyrrolyl or imidazolyl.
Suitable values of R9 include hydrogen, methyl, ethyl, propyl, n-butyl, benzyl, phenethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, carboxymethyl and carboxyethyl.
Preferred values of R10 in Formula I include hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl C2-10 aminoalkyl, C2-7 carboxyalkyl, mono(C1-4 alkyl)amino(C1-8)alkyl, and di(C1-4 alkyl)amino (C1-8)alkyl. Suitable values of R10 include methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, 2-carboxymethyl, 3-carboxyethyl, 4-carboxypropyl and 2-(dimethylamino)ethyl.
Preferred values of Ra, Rb and Rc in Formula I are hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano or xe2x80x94CO2Rw, where Rw, in each instance, is preferably one of C1-4 alkyl, C4-7 cycloalkyl or benzyloxycarbonyl. Suitable values of Ra, Rb and Rc include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, xe2x80x94CO2CH3, xe2x80x94CO2CH2CH3 and xe2x80x94CO2CH2CH2CH3. In the most preferred embodiments, Ra, Rb and Rc are each hydrogen.
Also preferred at Ra, Rb and Rc is the group xe2x80x94CO2Rw, where Rw is one of 
where Rd-Rh are defined as above. When Ra, Rb and Rc are xe2x80x94CO2Rw, where Rw is one of one of these moieties, the resulting compounds are prodrugs that possess desirable formulation and bioavailability characteristics. A preferred value for each of Rd, Re and Rg is hydrogen, Rf is methyl, and preferred values for Rh include benzyl and tert-butyl.
Preferred values of n in Formula I include from zero to 6, more preferably from zero to 4, and most preferably zero, 1 or 2. Preferred values of m include from zero to 4, more preferably zero, 1, 2 or 3.
Compounds having the following formulae (Formula IIA and Formula IIB) have been discovered to have exceptional potency as inhibitors of serine proteases: 
or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof, wherein:
R21 is one of phenyl, naphthyl, thiophenyl, quinolinyl or isoquinolinyl, optionally substituted by one or two substituents independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, methoxy, trifluoromethyl, cyano, nitro, amino or dimethylamino; and when R21 is phenyl, said phenyl can be optionally ortho-substituted by C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6)alkylsulfonyl, C6-10 arylsulfonamido, C6-10 ar(C1-6)alkylsulfonamido, N-morpholinosulfonyl, or R22R23NSO2xe2x80x94, where R22 and R23 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, or R22 and R23 can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholinosulfonyl, N-piperazinylsulfonyl (optionally Nxe2x80x2 substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of hydroxy, C1-8 alkanoyloxy, C1-6 alkoxy, C6-10 aryloxy, amino, mono- and di-C1-6 alkylamino, C1-8 alkanoylamino, C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, heterocycle, heterocycloalkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, formyl, C1-6 alkanoyl, C6-10 aroyl, C6-10 ar(C1-4)alkanoyl, sulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl;
R24 is hydrogen or C1-4 alkyl;
Yxe2x80x2 is one of O, NR10, where R10is defined as above, or a covalent bond;
a and b are 0, 1 or 2, preferably 1;
Xxe2x80x2 is 0 or NR29; and
R29 is hydrogen or C1-4 alkyl.
Preferred and suitable values of R21 are the same as those described above for R1; Yxe2x80x2 is preferably O; a is preferably one; and Xxe2x80x2 is preferably O or NH.
Specific compounds within the scope of the invention include the following:
3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine;
3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine;
3-[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine hydrochloride;
3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propoxyguanidine hydrochloride;
3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine hydrochloride;
3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(1,2,3,4-tetrahydroquinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidine acetate;
3-[5-hydroxymethyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidine acetic acid salt;
1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxyguanidine hydrochloride;
1-[[5-methyl-3-(2-cyanophenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxyguanidine acetate;
1-[[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropylmethoxyguanidine acetate;
{3-[5-Methyl-3-(2-(4-morpholinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyl}guanidine hydrochloride;
3-[5-methyl-3-(2-(acetylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methoxy-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-ethyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(phenylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
{3-[5-Methyl-3-(2-(4-ethyloxycarbonylpiperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine hydrochloride;
2-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethoxyguanidine;
2-hydroxy-3-[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxyguanidine;
3-[3-(2,4-bis(methylsulfonyl)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(3-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxyguanidine hydrochloride;
3-[3-((2-chloro-4-methylsulfonyl)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine hydrochloride;
3(3-(6-(2,3-Dihydro-1,1-dioxobenzo[b]thiophene)sulfonyloxy)-5-methylphenoxy)propoxy]guanidine trifluoroacetate;
{3-[5-Methyl-3-(2-(4-carboxylpiperin1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine;
3-[5-methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidine diacetate;
3-[5-methyl-3-[2-(N-hydroxy)aminophenylsulfonyloxy]phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-[2-aminophenylsulfonyloxy]phenoxy]propoxyguanidine hydrochloride;
3-[3-(2-(4-biphenylmethoxy)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine;
3-[3-(2-(3-biphenylmethoxy)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine hydrochloride;
1-[(3-benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethoxyguanidine;
3-[5-methyl-3-bis(2-methoxyethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(N-ethyl-3,4-(methylenedioxy)anilinosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-N-methyl-(3,4-dimethoxyphenyl)ethylaminosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-((3-ethoxycarbonyl-1-piperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-((3-carboxypiperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-((2-methoxycarbonyl-1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;
3-[5-methyl-3-((2-carboxy-1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(4-methylsulfonylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(4-(2-pyrimidinyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(N-methyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-methyl-N-(4-methoxyphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(4-ethylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(4-(piperidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-methyl-N-(2-(4-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-(ethoxycarbonylmethyl)-N-(2-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N,N-bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(4-(ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N,N-bis(carboxymethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;
3-[5-methyl-3-(2-(N-methyl-N-(4-carboxyphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;
3-[5-methyl-3-(2-(N-(2-carboxyethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;
3-[5-methyl-3-(2-(4-(carboxymethyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;
3-[5-methyl-3-(2-(4-(2-pyridyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(4-phenylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(4-benzylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(4-(2-methoxyphenyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;
3-[5-methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-benzyl-N-(2-(N,N-dimethylamio)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(2-(4-morpholinyl)ethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;
3-[5-methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;
3-[5-methyl-3-(2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;
3-[5-methyl-3-(2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;
3-[5-methyl-3-(2-(4-pyridylmethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;
N-methyl-N-{3-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine hydrochloride;
3-[3-methyl-5-(N-methyl-2-(methylsulfonyl)phenylsulfonylamino)phenoxy]propoxyguanidine hydrochloride;
3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]-propylaminoguanidine diacetate;
[3-[5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]-propylamino]guanidine hydrochloride;
[3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propylamino]guanidine acetate;
[3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]-propylamino]guanidine diacetate;
[3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propylamino]guanidine acetate;
as well as pharmaceutically acceptable salts thereof, for example the hydrochloride and acetate salts thereof. Structures for these compounds are provided in the pages prior to the claims.
Alternative embodiments of the present invention include compounds of Formula I in which two xe2x80x9cRxe2x80x9d groups together form a saturated or unsaturated hydrocarbon bridge, thus forming an additional cyclic moiety in the resulting compounds. Alternative embodiments include compounds of Formula I wherein Z, R1-R4, Y, m and n are as defined above; and:
A. R7 and R12 are taken together to form xe2x80x94(CH2)oxe2x80x94, where o is 1, 2 or 3;
R11 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl; R8 is hydrogen and R6, Ra, Rb and Rc are defined as above; or
B. R11 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, R7 is hydrogen;
R8 and R12 are taken together to form xe2x80x94(CH2)xe2x80x94(CH2)xe2x80x94(CH2)pxe2x80x94, where p is 1, 2 or 3; and
R6, Ra, Rb and Rc are defined as above; or
C. R6 and Rb are taken together to form xe2x80x94(CH2)xe2x80x94(CH2)rxe2x80x94 or xe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94NHxe2x80x94, where r is 1, 2 or 3;
Ra is hydrogen or hydroxy;
Rc is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbamoyloxy, cyano or xe2x80x94CO2Rwxe2x80x94, where Rw is as defined above;
R7, R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R8 are taken together to form xe2x80x94(CH2)yxe2x80x94, where y is zero, 1 or 2; or
D. Ra and Rc are taken together to form xe2x80x94CH2)xe2x80x94(CH2)sxe2x80x94, where s is 1 or 2;
R6 is hydrogen, alkyl, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or xe2x80x94CO2Rwxe2x80x94, where Rw is as defined above; and
R7, R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R8 are taken together to form xe2x80x94(CH2)yxe2x80x94, where y is zero, 1 or 2.
Thus, compounds having formulae III, IV, V and VI are contemplated: 
wherein R1-R4, Z, Y, R6-R12, Ra-Rc, n, m, o, p, r and s are defined as above. Preferred values for each of these variables are the same as described above for Formula I. Specific compounds within the scope of these formulae include: 
It is also to be understood that the present invention is considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in selected compounds of the present series.
The compounds of Formula I may also be solvated, especially hydrated. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over time due to the hygroscopic nature of the compounds.
Certain compounds within the scope of Formula I are derivatives referred to as prodrugs. The expression xe2x80x9cprodrugxe2x80x9d denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R. E., xe2x80x9cTheory and Practice of Prodrug Kinetics,xe2x80x9d Methods in Enzymology, 112:309-323 (1985); Bodor, N., xe2x80x9cNovel Approaches in Prodrug Design,xe2x80x9d Drugs of the Future, 6(3): 165-182 (1981); and Bundgaard, H., xe2x80x9cDesign of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities,xe2x80x9d in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, New York (1985). Useful prodrugs are those where Ra, Rb and/or Rc are xe2x80x94CO2Rw, where Rw is defined above. See, U.S. Pat. No. 5,466,811 and Saulnier et al., Bioorg. Med. Chem. Lett. 4:1985-1990 (1994).
The term xe2x80x9calkylxe2x80x9d as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.
The term xe2x80x9calkenylxe2x80x9d is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length.
The term xe2x80x9calkynylxe2x80x9d is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms in length.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
The term xe2x80x9calkoxyxe2x80x9d is used herein to mean a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
The term xe2x80x9carylxe2x80x9d as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
The term xe2x80x9cheteroarylxe2x80x9d as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14xcfx80 electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4xcex1H-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d as employed herein by itself or as part of another group refers to C1-6 alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
The term xe2x80x9ccycloalkylxe2x80x9d as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
The terms xe2x80x9calkoxyxe2x80x9d refers to any of the above alkyl groups linked to an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
The term xe2x80x9cmonoalkylaminexe2x80x9d as employed herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms.
The term xe2x80x9cdialkylaminexe2x80x9d as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms.
The term xe2x80x9chydroxyalkylxe2x80x9d as employed herein refers to any of the above alkyl groups substituted by one or more hydroxyl moieties.
The term xe2x80x9ccarboxyalkylxe2x80x9d as employed herein refers to any of the above alkyl groups substituted by one or more carboxylic acid moieties.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to mean a saturated or wholly or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Especially useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The term xe2x80x9cheteroatomxe2x80x9d is used herein to mean an oxygen atom (xe2x80x9cOxe2x80x9d), a sulfur atom (xe2x80x9cSxe2x80x9d) or a nitrogen atom (xe2x80x9cNxe2x80x9d). It will be recognized that when the heteroatom is nitrogen, it may form an NRyRz moiety, wherein Ry and Rz are, independently from one another, hydrogen or C1 to C8 alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring.
Another aspect of the present invention is a process for preparing an aminoguanidine compound of Formula I, comprising reacting an aminoguanidine of the formula 
wherein R6, Ra, Rb and Rc are defined as above, with a carbonyl-containing compound of the formula 
wherein R1-R4, Z, Y, n, m, R7, R8, R11 and R12 are defined as above to form an amidinohydrazone, and thereafter selectively reducing the hydrazone carbon to nitrogen double bond of the amidinohydrazone.
The aminoguanidine is typically provided as a salt, preferably the nitrate salt. The first step proceeds at ambient temperature using alcohol as a solvent. An acid, such as 4N HCl in dioxane is added to the reaction mixture. The reaction is more fully described herein.
Another aspect of the present invention is a process for preparing a hydroxyguanidine compound of Formula I, comprising reacting an alkoxyamine compound of the formula 
wherein R1-R4, Z, Y, n, m, R7, R8, R11 and R12 are defined as above with a guanidinylating reagent. Preferred guanidinylating reagents include: aminoiminosulfonic acid, optionally substituted 1H-pyrazole-1-carboxamidines, or N,Nxe2x80x2-bis(tert-butoxycarbonyl) S-methyl isothiourea.
The invention is also directed to alkoxyamine intermediates that are useful for forming the protease inhibiting compounds of Formula I. These intermediates are represented by Formula IX: 
wherein R1-R4, Z, Y, n, m, R7, R8, R11 and R12 are defined as above for Formula I.
Schemes Ia, Ib, and Ic outline the synthetic steps to produce compounds of the present invention where R1xe2x80x94Z is R1xe2x80x94C(RyRz)2Oxe2x80x94 or R1xe2x80x94O2Oxe2x80x94. Scheme Ia illustrates but is not limited to the preparation of the compounds of Examples 1-8, 10-18, 21-22, 28-33, and 82-86. 
Phenols 1 (where Pa=H) are converted to monosulfonates 2 by treatment with appropriate sulfonyl chlorides. Preferred conditions include treating phenol 1 with a sulfonyl chloride in a biphasic system composed of an organic solvent, such as an ether, and an aqueous phase saturated with NaHCO3. Alternatively, the reaction may be effected first by deprotonating 1 with one equivalent of a strong base, most preferably NaH, in a polar organic solvent, such as N,N-dimethylformamide or tetrahydrofuran, followed by treating the deprotonated phenol with the sulfonyl chloride. Still alternatively, phenol 1, in a typical organic solvent, such as dichloromethane, may be converted to 2 by treating the phenol with sulfonyl chloride in the presence of an amine base, such as 4-methylmorpholine.
Phenols 1 may be monoprotected (Pa is a protecting group) with a variety of protecting groups known in the art, such as esters and benzyl ethers (Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, Inc. New York (1991)). Deprotection of the hydroxy groups is routinely accomplished using the reaction conditions well known in the art. For example, deprotection of benzyl ethers may be effected through catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran. Deprotection of an acetate is accomplished by basic hydrolysis, most preferably with sodium hydroxide in aqueous tetrahydrofuran.
Phenols 2 are coupled to 3 (for L=OH) using a Mitsunobu coupling procedure (Mitsunobu, O., Synthesis 1 (1981)), where Pb of 3 may be a suitable alcohol protecting group. Alternatively, suitable diols (Pb=H) may be used in the Mitsunobu reaction. Preferred coupling conditions include using a trialkylphosphine or triarylphosphine, such as triphenylphosphine or tri-n-butylphosphine, in a suitable solvent, such as tetrahydrofuran or dichloromethane, and an azodicarbonyl reagent, such as diethyl azodicarboxylate or 1,1xe2x80x2-(azodicarbonyl)dipiperidine. Typical Pb (where Pb is an alcohol protecting group) is well known in the art, such as esters and benzyl ethers (Greene, T. W. and Wuts, P. G. M., supra). Alternatively, where L is a reactive leaving group such as halide or sulfonate, phenol 2 may be treated with a base, such as sodium hydride, in a solvent, such as N,N-dimethylformamide, and then treated with 3. Removal of Pb is routinely accomplished using the reaction conditions well known in the art. For example, deprotection of benzyl ethers may be effected through catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran. Deprotection of an acetate is accomplished by basic hydrolysis, most preferably with sodium hydroxide in aqueous tetrahydrofuran.
Alternatively still, alcohol 4 can be obtained by reduction of the appropriate aldehyde or ketone 7 (obtained from 2 as described below) with a suitable reducing agent, such as sodium or lithium borohydride (Wallbridge, J. Prog. Inorg. Chem 11:99-231(1970)).
Alcohol 4 is converted to 9 employing a Mitsunobu reaction with an N-hydroxycyclic imide derivative such as N-hydroxyphthalimide. Unveiling of the phthalimide protecting group is accomplished using standard conditions well known in the art (Greene, T. W. and Wuts, P. G. M., supra), for example, sodium borohydride in a mixture of an appropriate alcohol (e.g. ethanol or 2-propanol)/water followed by acidification. Alternatively, removal of the protecting group may be accomplished using hydrazine or methylamine.
Guanidinylation of the resulting alkoxyamine to 10 is achieved using standard reagents such as aminoiminosulfonic acid (Miller, A. E. and Bischoff, J. J. Synthesis 777 (1986)), or 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M. S. et. al. J. Org. Chem 57(8):2497 (1992)), or with substituted guanidinylating reagents such as N,Nxe2x80x2-bis(tert-butoxycarbonyl)-S-methylisothiourea (Bergeron, R. J. and McManis, J. S. J. Org. Chem. 52:1700 (1987)) or Nxe2x80x94Ra, Nxe2x80x94Rb, Nxe2x80x2xe2x80x94Rc-1H-pyrazole-1-carboxamidine, where Ra, Rb and Rc are defined as above for Formula I. Useful 1H-pyrazole-1-carboxamidines include N,Nxe2x80x2-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and N,N xe2x80x2-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (all of which can be prepared according to Bernatowicz, M. S. et. al., Tetrahedron Letters 34:3389 (1993)).
Conversion of alcohol 4 to the corresponding aldehyde or ketone 7 is accomplished using routine procedures for the oxidation of alcohols (see for example Carey, F. A, Sundberg, R. J. Advanced Organic Chemistry, Part B: Reactions and Synthesis, 3rd edition, Plenum Press, New York (1990)) such as the Swern oxidation (Mancuso, A. J. et al., Journal of Organic Chemistry 3329 (1976)) pyridinium chlorochromate (Corey, E. J. and Suggs, J. W. Tetrahedron Letters 2647 (1975)) pyridinium dichromate (Corey, E. J. and Schmidt, G. Tetrahedron Letters 399 (1979)), or sulfur trioxide pyridine complex/dimethylsulfoxide (Tetrahedron Letters 28:1603 (1987)).
Still alternatively, 2 may be coupled directly to 5 where L=OH or a reactive leaving group such as halide, alkyl sulfonate, or aryl sulfonate. In the case of L=OH, the Mitsunobu coupling procedure may be used. In cases where L is a reactive leaving group such as halide or sulfonate, phenol 2 may be treated with a base, such as sodium hydride, in a solvent, such as N,N-dimethylformamide, and then treated with 5.
Alternatively, phenol 2 may be converted to 7 by the Mitsunobu reaction using 6 wherein L=OH and Pc is an aldehyde, or ketone protecting group which is well known in the art (Greene, T. W. and Wuts, P. G. M., supra), for example, a dimethyl ketal or acetal, 1,3-dioxolane group, or 1,3-dioxane group. Alternatively, where L of 6 is a reactive leaving group such as halide or sulfonate, phenol 2 may be treated with a base, such as sodium hydride in a solvent such as N,N-dimethylformamide, and then treated with 6. Pc may then be removed to afford 7 using standard conditions well known in the art, for example, p-toluenesulfonic acid in acetone (Greene, T. W. and Wuts, P. G. M., supra).
Compound 7 is then converted to amidinohydrazone 8 using standard conditions, for example, treatment with an aminoguanidine, such as aminoguanidine or 2-hydrazinoimidazoline, optionally in the presence of an acid such as nitric acid, hydrogen chloride, or hydrogen bromide, in an appropriate solvent, for example, ethanol or methanol, which, in addition, may contain other solvents such as dichloromethane or tetrahydrofuran. Conversion of 8 to 11 is accomplished under reducing conditions well known in the art, for example, lithium borohydride in an appropriate solvent such as tetrahydrofuran or methanol at various temperatures up to reflux. As an alternative method, catalytic hydrogenation with palladium on carbon catalyst can be employed.
When Ra, Rb and/or Rc are a protecting group, for example t-butyloxycarbonyl (Boc), these protecting groups can be optionally removed by treatment with acid, usually trifluoroacetic acid in a suitable solvent such as dichloromethane or water, or by HCl gas dissolved in a suitable solvent, such as 1,4-dioxane. 
A variation of Scheme Ia (Scheme Ib) involves the use of monoprotected phenols in the synthesis of Examples 19-20, 23-26, and 80. Phenols 1 are monoprotected (Pa is a protecting group) with a variety of protecting groups known in the art such as esters and benzyl ethers (Greene, T. W. and Wuts, P. G. M., supra). Monoprotected phenols 1 are coupled to 3 as described for Scheme Ia. Deprotection and another Mitsunobu coupling with an N-hydroxy imide derivative, such as N-hydroxyphthalimide, as described for Scheme Ia, gives the alkoxyphthalimides 16. The removal of the phthalimide group, as described for Scheme Ia, produces the alkoxyamine. The alkoxyamines are subsequently converted to the optionally protected alkoxyguanidines, using the standard guanidinylation reagents, such as aminoiminosulfonic acid (Miller, A. E. and Bischoff, J. J., supra) or 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M. S. et. al., supra), or with substituted guanidinylating reagents such as N,Nxe2x80x2-bis(tert-butoxycarbonyl)-S-methylisothiourea (Bergeron, R. J. and McManis, J. S., supra) or Nxe2x80x94Ra, Nxe2x80x94Rb, Nxe2x80x2Rc-1H-pyrazole-1-carboxamidine including N,Nxe2x80x2-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and N,Nxe2x80x2-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (all of which can be prepared according to (Bernatowicz, M. S. et. al., supra) where Ra, Rb and Rc are as defined above. The phenolic protecting group, Pa, may be removed to give 17 and the resultant phenolic group reacted with sulfonyl chlorides. Optionally, the protected alkoxyguanidines may be alkylated on the unprotected nitrogen of the guanidine using a Mitsunobu coupling with an alcohol R6OH (e.g., methanol gives the N-methyl alkoxyguanidine derivative). Finally, the guanidine protecting groups, Ra, Rb, and Rc, may be removed as outlined for Scheme Ia. 
Scheme Ic outlines the synthesis of the 1,2-benzenedisulfo derivatives described in Examples 34-79. In particular, Examples 34-68 were synthesized by the reaction of 1,2-benzenedisulfonic anhydride 18 (Koeberg-Telder et al., J. Chem. Soc. Perkin II 98 (1973)) with secondary amines, R13R14NH, in the presence of a base such as a tertiary amine where R13 and R14 are as defined above, provided that they are both other than hydrogen. The resultant monosulfonic acid salt is converted to the sulfonyl chloride in situ by reaction with 1 equivalent of oxalyl chloride. The resultant sulfonyl chloride is reacted in situ with the phenol 17. The optional guanidine protecting groups, Ra, Rb, and Rc, may be removed as outlined for Scheme Ia to give 19.
The Examples of 68-79 were alternatively synthesized by the reaction of the benzenedisulfonic anhydride 18 with the O-phthalimide 16 (Pa=H). The resultant monosulfonic acid salt is converted in situ to the sulfonyl chloride with 1 equivalent of oxalyl chloride. The resultant sulfonyl chloride is reacted with amines, especially primary and diamines, to produce sulfonamides. The O-amine is next deprotected and guanidinylated by the means outlined for Scheme Ia. Finally, the optional guanidine protecting groups, Ra, Rb, and Rc, may be removed as outlined for Scheme Ia to give 19. 
Schemes IIa and IIb outline the syntheses of primary and secondary sulfonamidophenoxy derivatives and carboxamido derivatives, where R1xe2x80x94Zxe2x80x94 is R1xe2x80x94SO2NR10xe2x80x94 or R1xe2x80x94CONR10xe2x80x94.
Scheme IIa outlines the synthesis of intermediate 1,3-aminophenols which are further converted to sulfonamidophenoxy derivatives where R1xe2x80x94Z is R1xe2x80x94SO2NR10xe2x80x94 and R10 is preferably an alkyl group, as exemplified by Example 81, or are alternatively converted to carboxamidophenoxy derivatives where R1xe2x80x94Z is R1xe2x80x94CONR10xe2x80x94. Phenols 1 are reacted with 2-bromo-2-methyl propanamide in the presence of a base, such as sodium hydride, to give the aryloxyamides 20. The aryloxyamides 20 are treated with sodium hydride in a high boiling solvent, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, at an elevated temperature (e.g., 100xc2x0 C. for 3 h) and undergo the Smiles rearrangement to the anilides 21 (Cotts and Southcott, J. Chem. Soc. PT 1 767 (1990)). The anilides 21 are hydrolyzed using strong base and elevated temperature (e.g., 10N sodium hydroxide at reflux) for extended times (e.g., 2 days) in order to provide the corresponding anilines 22. The anilines 22 are converted to sulfonamides 23 by the reaction with sulfonyl chlorides in the presence of a suitable base, such as a tertiary amine. The sulfonamides 23 are reacted with base (e.g., cesium carbonate) and R10L where L is a reactive leaving group, such as halide or sulfonate. Alternatively, the anilines 22 are converted to carboxamides by the reaction with acyl chlorides (R1COCl) in the presence of a suitable base such as a tertiary amine. Still alternatively, the carboxamides may be produced by the reaction of anilines 22 with carboxylic acids (R1COOH) by any of the known peptide coupling reagents, such as 1,3-dicyclohexylcarbodiimide or Castro""s reagent (BOP) (Castro B., et al., Tetrahedron Lett. 1219 (1975)). The phenolic protecting group, Pa, is then removed and the resultant phenols 24 are coupled with 3 as described for Scheme Ia. After removal of the alcohol protecting group, Pb, the alcohol is coupled to N-hydroxy imides, such as N-hydroxyphthalimide, as described for Scheme Ia. The removal of the phthalimide group, as described for Scheme Ia, produces the alkoxyamine. The alkoxyamines are subsequently converted to the optionally protected alkoxyguanidines, using the standard guanidinylation reagents outlined for Scheme Ia. Finally, the guanidine protecting groups, Ra, Rb, and Rc, may be optionally removed as outlined for Scheme Ia to produce the target 27. 
An alternative method to synthesize sulfonamides, especially unalkylated sulfonamides (where R10=H) is shown in Scheme IIb. Nitrophenol 28 is coupled to 3 by standard techniques. Preferably, the reaction is effected by the Mitsunobu reaction (where L is OH). Alternatively, the nitrophenol is treated with a base, such as NaH, in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran, followed by the addition of 3 (where L is a reactive group, such as Cl, Br, I or sulfonate). After Pb group removal, the alcohol 29 undergoes a Mitsunobu coupling with an N-hydroxy imide, such as N-hydroxyphthalimide, as described in Scheme Ia. The nitro group of 30 is thereafter reduced, for example, by catalytic reduction using palladium on carbon in a suitable solvent such as ethanol or tetrahydrofuran. The resulting product is treated with an appropriate sulfonyl chloride (R1SO2Cl) to provide the sulfonamide 31. At this point, the sulfonamide group may be optionally alkylated as described in Scheme IIa. Alternatively, the resulting product from nitro reduction is treated with an appropriate acyl chloride (R1COCl) to provide the corresponding carboxamide 31. Still alternatively, the carboxamides 31 may be produced by the reaction of the product from nitro reduction with carboxylic acids (R1COOH) by any of the known peptide coupling reagents, such as 1,3-dicyclohexylcarbodiimide or Castro""s reagent (BOP). Removal of the O-amine protecting group and guanidinylation of the O-amine are accomplished by methods described in Scheme Ia. Finally, the O-guanidine protecting groups, Ra, Rb, and Rc, may be removed as outlined in Scheme Ia to give the target 32. 
The compounds of the present invention where R1xe2x80x94Z is R1xe2x80x94CH(RyRz)NR10xe2x80x94 can be synthesized by the steps outlined in Scheme IIc. Aniline 22 is converted to 33, where Rx is H, by reductive amination with a suitable carbonyl component, R1CORy. The preferred reducing agent is tetramethylammonium triacetoxyborohydride. Alternatively, sodium triacetoxyborohydride or sodium cyanohydride may be used. Still alternatively, reductive amination may be carried out by forming an imine (Schiff base) between the amine and the carbonyl component using a catalytic amount of acid such as p-toluenesulfonic acid, followed by reduction with sodium borohydride. Still alternatively, the imine may be reduced using catalytic hydrogenation using a catalyst such as palladium on carbon in standard solvent such as ethanol. As an alternate to a reductive amination, aniline 22 may be reacted with R1(RyRx)L, where L is a reactive leaving group, such as halide or sulfonate. The remaining conversion of 33 to 37, which comprises of Pa removal, coupling to 3. Pb removal and coupling to a N-hydroxy imide, deprotection of O-amine, guanidinylation and optional deprotection of the guanidine group, is similar to those steps detailed for the conversion of 23 to 27 in Scheme IIa. 
Additionally, compounds of the present invention where Y is NR10 and R1xe2x80x94Z is R1xe2x80x94SO2NR10xe2x80x94 or R1xe2x80x94CONR10xe2x80x94 can be prepared by Scheme III. Nitroaniline 38 is converted to a sulfonamide by treatment with an appropriate sulfonyl chloride R1SO2Cl in the presence of a weak base, such as a tertiary amine. The resulting sulfonamide or carboxamide nitrogen can be alkylated with a suitable alkylating agent R10L as described in Scheme IIa to provide intermediate 39. Alternatively, 38 is treated with an appropriate acyl chloride (R1COCl) to provide the corresponding carboxamide 39. Still alternatively, the carboxamides 39 may be produced by the reaction of 38 with carboxylic acids (R1COOH) by any of the known peptide coupling reagents, such as 1,3-dicyclohexylcarbodiimide or Castro""s reagent (BOP). After reduction of the nitro group, as described in Scheme IIb, the resulting aniline is coupled with aldehyde 40 preferably under reductive amination conditions to give 41. The preferred reducing agent is tetramethylammonium triacetoxyborohydride. Alternatively, sodium triacetoxyborohydride or sodium cyanohydride may be used. Still alternatively, reductive amination may be carried out by forming an imine (Schiff base) between the amine and the carbonyl component using a catalytic amount of acid such as p-toluenesulfonic acid, followed by reduction with sodium borohydride. Still alternatively, the imine may be reduced using catalytic hydrogenation using a catalyst such as palladium on carbon in standard solvent such as ethanol. Finally, the O-guanidine protecting groups, Ra, Rb, and Rc, of 41 may be removed as outlined in Scheme Ia to give 42. 
As an alternative scheme to produce the O-phthalamide-containing intermediates 9, 16, 26, 31, and 36, the respective phenols 2, 1, 24, 28, and 34 may be reacted under basic conditions with reagent 43 which contains a leaving group L. This scheme is limited to producing compounds where R12 is hydrogen. Reagent 43 is produced by reacting a compound having two leaving groups, L, and Lxe2x80x2 under basic conditions with N-hydroxyphthalimide (Khadilkar and Samant, Indian J. Chem. Sec. B 1137 (1993)).
Compounds wherein Ra and Rc together form a cyclic group, such as an imidazoline, can be synthesized by employing an imidazoline in place of the aminoguanidine in the above Schemes.
Compounds wherein R7 and R12 or R8 and R12 together form a methylene linkage can be synthesized by substituting a cyclic ketone having a reactive group L that is attached directly or indirectly to the carbocyclic ring. Examples of suitable reagents include 2-hydroxycyclopentanone, 3-hydroxycyclopentanone, 2-hydroxycyclohexanone and 3-hydroxycyclohexanone.
Compounds VI wherein R6 and Rb are taken together with the nitrogens to which they are attached to form a ring structure are prepared by substituting a heterocyclic amine 12 (below) for the aminoguanidine in the above Schemes. 
Compounds wherein R9 and Rb are taken together with the nitrogen atoms to which they are attached to form an imidazoline moiety are prepared by substituting a 2-hydrazinoimidazoline 13 (above) for the aminoguanidines in the above Schemes.
For medicinal use, the pharmaceutically acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred. The acid addition salts are obtained either by reaction of an organic base of Formula I with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any practitioner skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids are hydrohalide acids such as HCl, HBr, HI; sulfuric acid; phosphoric acid and the like. Preferred acids for forming acid addition salts include HCl and acetic acid.
The compounds of the present invention represent a novel class of potent inhibitors of metallo, acid, thiol and serine proteases. Examples of the serine proteases inhibited by compounds within the scope of the invention include leukocyte neutrophil elastase, a proteolytic enzyme implicated in the pathogenesis of emphysema; chymotrypsin and trypsin, digestive enzymes; pancreatic elastase, and cathepsin G, a chymotrypsin-like protease also associated with leukocytes; thrombin and factor Xa, proteolytic enzymes in the blood coagulation pathway. Inhibition of thermolysin, a metalloprotease, and pepsin, an acid protease, are also contemplated uses of compounds of the present invention. The compounds of the present invention are preferably employed to inhibit trypsin-like proteases.
An end use application of the compounds that inhibit chymotrypsin and trypsin is in the treatment of pancreatitis. For their end-use application, the potency and other biochemical parameters of the enzyme-inhibiting characteristics of the compounds of the present invention is readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity of the disease state of the patient or animal to be treated, as determined by the attending diagnostician. It is expected that a useful dose range will be about 0.01 to 10 mg per kg per day for an effective therapeutic effect.
Compounds of the present invention that are distinguished by their ability to inhibit either factor Xa or thrombin may be employed for a number of therapeutic purposes. As factor Xa or thrombin inhibitors, compounds of the present invention inhibit thrombin production. Therefore, these compounds are useful for the treatment or prophylaxis of states characterized by abnormal venous or arterial thrombosis involving either thrombin production or action. These states include, but are not limited to, deep vein thrombosis; disseminated intravascular coagulopathy which occurs during septic shock, viral infections and cancer; myocardial infarction; stroke; coronary artery bypass; fibrin formation in the eye; hip replacement; and thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PCTA).
Other uses include the use of said thrombin inhibitors as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. The compounds of the present invention may also be used as an anticoagulant in extracorporeal blood circuits.
Metal stents have been shown to reduce restenosis, but are thrombogenic. A strategy for reducing the thrombogenicity of stents is to coat, embed, adsord or covalently attach a thrombin-inhibiting agent to the stent surface. The compounds of the present invention can be employed for this purpose. Compounds of the invention can be attached to, or embedded within soluble and/or biodegradeable polymers as and thereafter coated onto stent materials. Such polymers can include polyvinylpyrrolidone, polyhydroxy-propylmethacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. See European Application 761 251, European Application 604,022, Canadian Patent 2,164,684 and PCT Published Applications WO 96/11668. WO 96/32143 and WO 96/38136.
By virtue of the effects of both factor Xa and thrombin on a host of cell types, such as smooth muscle cells, endothelial cells and neutrophils, the compounds of the present invention find additional use in the treatment or prophylaxis of adult respiratory distress syndrome; inflammatory responses; wound healing; reperfusion damage; atherosclerosis; and restenosis following an injury such as balloon angioplasty, atherectomy, and arterial stent placement. The compounds of the present invention may be useful in treating neoplasia and metastasis as well as neurodegenerative diseases, such as Alzheimer""s disease and Parkinson""s disease.
When employed as thrombin or factor Xa inhibitors, the compounds of the present invention may be administered in an effective amount within the dosage range of about 0.1 to about 500 mg/kg, preferably between 0.1 to 10 mg/kg body weight, on a regimen in single or 2-4 divided daily doses.
When employed as inhibitors of thrombin, the compounds of the present invention may be used in combination with thrombolytic agents such as tissue plasminogen activator, streptokinase, and urokinase. Additionally, the compounds of the present invention may be used in combination with other antithrombotic or anticoagulant drugs such as, but not limited to, fibrinogen antagonists and thromboxane receptor antagonists.
Human leucocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states. Compounds of the present invention are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. The leucocyte elastase inhibitory properties of compounds of the present invention are determined by the method described below. Cathepsin G has also been implicated in the disease states of arthritis, gout and emphysema, and in addition, glomerulonephritis and lung infestations caused by infections in the lung. In their end-use application the enzyme inhibitory properties of the compounds of Formula I is readily ascertained by standard biochemical techniques that are well-known in the art.
The Cathepsin G inhibitory properties of compounds within the scope of the present invention are determined by the following method. A preparation of partially purified human Cathepsin G is obtained by the procedure of Baugh et al., Biochemistry 15: 836 (1979). Leukocyte granules are a major source for the preparation of leukocyte elastase and cathepsin G (chymotrypsin-like activity). Leukocytes arc lysed and granules are isolated. The leukocyte granules are extracted with 0.20 M sodium acetate, pH 4.0, and extracts are dialyzed against 0.05 M Tris buffer, pH 8.0 containing 0.05 M NaCl overnight at 4xc2x0 C. A protein fraction precipitates during dialysis and is isolated by centrifugation. This fraction contains most of the chymotrypsin-like activity of leukocyte granules. Specific substrates are prepared for each enzyme, namely N-Suc-Ala-Ala-Pro-Val-p-nitroanilide and Suc-Ala-Ala-Pro-Phe-p-nitroanilide. The latter is not hydrolyzed by leukocyte elastase. Enzyme preparations are assayed in 2.00 mL of 0.10 M Hepes buffer, pH 7.5, containing 0.50 M NaCl, 10% dimethylsulfoxide and 0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide as a substrate. Hydrolysis of the p-nitroanilide substrate is monitored at 405 nm and at 25xc2x0 C.
Useful dose range for the application of compounds of the present invention as neutrophil elastase inhibitors and as Cathepsin G inhibitors depend upon the nature and severity of the disease state, as determined by the attending diagnostician, with a range of 0.01 to 10 mg/kg body weight, per day, being useful for the aforementioned disease states.
Compounds of the present invention that inhibit urokinase or plasminogen activator are potentially useful in treating excessive cell growth disease state. As such compounds of the present invention may also be useful in the treatment of benign prostatic hypertrophy and prostatic carcinoma, the treatment of psoriasis, and as abortifacients. For their end-use application, the potency and other biochemical parameters of the enzyme inhibiting characteristics of compounds of the present invention are readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for this application will depend upon the nature and severity of the disease state of the patient or animal to be treated as determined by the attending diagnostician. It is to be expected that a general dose range will be about 0.01 to 10 mg per kg per day for an effective therapeutic effect.
Additional uses for compounds of the present invention include analysis of commercial reagent enzymes for active site concentration. For example, chymotrypsin is supplied as a standard reagent for use in clinical quantitation of chymotrypsin activity in pancreatic juices and feces. Such assays are diagnostic for gastrointestinal and pancreatic disorders. Pancreatic elastase is also supplied commercially as a reagent for quantitation of xcex11-antitrypsin in plasma. Plasma xcex11-antitrypsin increases in concentration during the course of several inflammatory diseases, and xcex11-antitrypsin deficiencies are associated with increased incidence of lung disease. Compounds of the present invention can be used to enhance the accuracy and reproducibility of these assays by titrametric standardization of the commercial elastase supplied as a reagent. See, U.S. Pat. No. 4,499,082.
Protease activity in certain protein extracts during purification of particular proteins is a recurring problem which can complicate and compromise the results of protein isolation procedures. Certain proteases present in such extracts can be inhibited during purification steps by compounds of the present invention, which bind tightly to various proteolytic enzymes.
The pharmaceutical compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes. Alternatively, or concurrently, administration can be by the oral route. The dosage administered will be dependent upon the age, health, and Weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
In addition to the pharmacologically active compounds, the new pharmaceutical reparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
The pharmaceutical preparations of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as, acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatte oils or liquid paraffin. In addition, stabilizers may be added.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, alkaline solutions and cyclodextrin inclusion complexes. Especially preferred salts are hydrochloride and acetate salts. One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of compounds of the present invention. Useful cyclodextrins for this purpose are disclosed in U.S. Pat. Nos. 4,727,064, 4,764,604, and 5,024,998.
In addition, suspensions of the active compounds as appropriate oily injection suspensions can be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.